Studies in both hypertensive patients and healthy volunteers have shown that blacks are less responsive to beta-blocker therapy than whites. It has recently been shown that blacks have significantly lower plasma concentrations of propranolol than whites, a finding consistent with these response differences. The overall objective of the current proposal is to investigate the mechanisms responsible for the racial differences in propranolol kinetics and to evaluate the impact of kinetic differences on response. The possible explanations for racial differences in oral propranolol kinetics (systemic clearance, absorption or hepatic first pass metabolism) will be evaluated by simultaneous determination of intravenous (IV) and oral propranolol kinetics. This will be accomplished by simultaneous administration of IV radiolabelled propranolol and oral unlabelled propranolol at steady state, with determination of plasma concentrations by chiral HPLC. It seems most likely the differences will be due to differences in hepatic first pass metabolism, therefore clearance through the three primary metabolic pathways of propranolol will also be characterized. Gender differences in propranolol kinetics have been documented in whites. Inclusion in this study of black and white men and women will allow for evaluation of racial differences in each gender and gender differences in the two races. The results of this study are important because they will provide information about the disposition of a widely used drug, and also because they may be suggestive of other drugs which may exhibit racial differences in their kinetics. For example, one of the metabolic pathways responsible for propranolol metabolism is also known to metabolize at least 30 other drugs. Racial differences in this pathway would be suggestive of racial differences in kinetics for all these other drugs. Studies in hypertensive patients receiving oral propranolol have shown that whites have a 30-60% greater response than blacks while studies in healthy volunteers receiving IV propranolol have shown de whites have an approximately 20% greater response than blacks. While oral propranolol therapy results in racial differences in plasma concentration, IV propranolol does not. Thus pharmacokinetics may explain the larger magnitude in racial response differences in patients compared to volunteers. Alternatively, racial differences in hypertension pathophysiology may be responsible for the larger racial difference. The impact of pharmacokinetics on response differences will be evaluated by measuring exercise heart rate responses in healthy volunteers following oral propranolol therapy. Knowledge of whether racial differences in beta-blocker response are due to physiologic or pathophysiologic differences between blacks and whites is important for understanding the response differences, and may ultimately be related to the higher prevalence of hypertension in blacks.